Traumatic brain injury (TBI) is a major public health problem associated with pathophysiological mechanisms linked with progressive structural and long-term functional consequences. Although many of the molecular events underlying cellular susceptibility and functional deficits after TBI have been characterized, the successful translation of therapies to the clinic has been unsuccessful. One reason for these translational failures is the appreciation that TBI is not a single acute event but a chronic disease process that necessitates a polytherapeutic approach targeting both acute and chronic injury events. Targeted temperature management (TTM) protocols, including therapeutic hypothermia protect the microenvironment after trauma and may promote reparative mechanisms. In addition, classes of molecules have been recently identified that promote neurogenic processes and enhance cognitive recovery. Compounds including the highly-active agent P7C3-A20 have favorable pharmacological profiles and augment both hippocampal neurogenesis and the survival of newborn neurons. We have recently reported that early cooling and P7C3-A20 treatment each individually is neuroprotective and enhance reparative processes at early intervals after TBI. These findings emphasize that therapeutic hypothermia and neurogenic compounds are pertinent therapeutic interventions to augment protection and promote regenerative mechanisms that contribute to cognition. The goal of this proposal is to test the hypothesis that posttraumatic hypothermia and the P7C3 class of molecules act by targeting a range of mechanisms in terms of their respective protective and reparative properties and that the combination of these treatments will lead to superior preservation of hippocampal-dependent memory. The first Aim is to characterize the effects hypothermia and hyperthermia has on microglia/macrophage phenotypes and reparative processes. Two complementary TBI models using rats and transgenic mice with cutting edge 3D imaging will examine the functions of adult neurogenesis. The Nestind-TK-GFP transgenic mice will allow neurogenesis to be independently manipulated to assess causal links to functional improvement with treatments. Aim 2 will test the translational potential of P7C3-A20 using rat and mouse transgenic models to again independently manipulate neurogenesis and relate to functional outcome. Based on the newly proposed binding properties of this class of molecules to nicotinamide phosphoribosyltransferase, an important step for the production of nicotinamide adenosine dinucleotide, we will evaluate the treatment effects on this metabolic pathway as an essential mechanism of protecting hippocampal precursor cells. Finally, Aim 3 will test whether a novel combinatorial treatment with therapeutic hypothermia and P7C3-A20 leads to greater cytoprotection, hippocampal neurogenesis and improved cognitive function relative to single treatments. These studies will help clarify mechanisms underlying posttraumatic temperature modifications and proneurogenic therapies and thereby preserving the microenvironment, hippocampal neurogenesis and memory function.